Figure - available from: Journal of Thrombosis and Thrombolysis
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TEM of wild type and Ala427Thr AT: a wild type AT incubated at 60 °C for 0 min, b 30 min, c 90 min and Ala427Thr variant AT incubated at 60 °C for d 0 min, e 30 min and f 90 min
Source publication
Antithrombin (AT) deficiency is a rare but strong risk factor for the thrombosis development. Mutations in gene encoding AT (SERPINC1) have provided a detailed understanding of AT deficiency and subsequent development of thrombotic complications. In the present study, we describe a case of thrombotic patient with reduced AT activity and normal AT a...
Citations
Thromboembolic diseases are a major cause of mortality in human and the currently available anticoagulants are associated with various drawbacks, therefore the search for anticoagulants that have better safety profile is highly desirable. Compounds that are part of the dietary routine can be modified to possibly increase their anticoagulant potential. We show mannose 2,3,4,5,6-O-pentasulfate (MPS) as a synthetically modified form of mannose that has appreciable anticoagulation properties. An in silico study identified that mannose in sulfated form can bind effectively to the heparin-binding site of antithrombin (ATIII) and heparin cofactor II (HCII). Mannose was sulfated using a simple sulfation strategy-involving triethylamine-sulfur trioxide adduct. HCII and ATIII were purified from human plasma and the binding analysis using fluorometer and isothermal calorimetry showed that MPS binds at a unique site. A thrombin inhibition analysis using the chromogenic substrate showed that MPS partially enhances the activity of HCII. Further an assessment of in vitro blood coagulation assays using human plasma showed that the activated partial thromboplastin time (APTT) and prothrombin time (PT) were prolonged in the presence of MPS. A molecular dynamics simulation analysis of the HCII-MPS complex showed fluctuations in a N-terminal loop and the cofactor binding site of HCII. The results indicate that MPS is a promising lead due to its effect on the in vitro coagulation rate.
Communicated by Ramaswamy H. Sarma
Background
Antithrombin (AT) is the primary physiological anticoagulant of normal hemostasis. Hereditary AT deficiency, an autosomal dominant thrombotic disease caused by mutations in the AT gene (SERPINC1), is associated with venous thromboembolism.
Objective
We investigated the phenotypes, genotypes, and pathogenesis of hereditary AT deficiency in a 12-year-old boy (proband) who developed a pulmonary embolism and a subsequent deep vein thrombosis.
Methods
The AT activity and AT antigen level of the proband and his family members were measured. Mutation sites in all seven exons of SERPINC1 were identified. Analysis of conserved regions around codon 426 of the SERPINC1 gene and functional predictions were performed using bioinformatics tools.
Results
The proband, his father, and his paternal grandmother demonstrated reduced AT activity and antigen levels consistent with Type I AT deficiency. A novel heterozygous missense mutation, c.1385G >A (Cys462Tyr) was identified in all three symptomatic family members. This missense mutation causes disruption of the 279Cys-462Cys disulfide bond and leads to type Ⅰ hereditary AT deficiency.
Conclusion
A SERPINC1 missense mutation (Cys426Tyr) causing damage to the 279Cys-462Cys disulfide bond of the AT protein appears to be the cause of Type I AT deficiency in this family. These findings indicate one pathological mechanism associated with hereditary AT deficiency.
